Section N: Infiltrative Immunologic

PATIENT STORY

A 39-year-old woman presents with raised rings on her right hand. Not knowing the correct diagnosis, another physician prescribed topical steroids and antifungal medicines with no benefit. The diagnosis of granuloma annulare (GA) was made by the typical clinical appearance, and the patient was offered intralesional steroids. Triamcinolone acetonide was injected as seen in Figure 182-1A. The patient noted improvement over the subsequent weeks, but within a month new lesions began to appear on her other hand (Figure 182-1B). Additional injections were provided and 1 month later the patient had regression of the treated lesions but had new lesions on the right arm (Figure 182-2A). At the next visit, the patient had new lesions on her feet as well (Figure 182-2B). The diagnosis of disseminated GA was made and systemic treatment was started.

INTRODUCTION

GA is a common dermatologic condition that presents as small, light-red, dermal papules coalescing into annular plaques without scale. As in the above vignette, it is often mistaken for nummular eczema or tinea corporis. Distribution, pattern, and lack of scale are important diagnostic clues.

EPIDEMIOLOGY

• GA affects twice as many women as men.¹

• The four presentations of GA are localized, disseminated/generalized, perforating, and subcutaneous.

• Of the four variations, the localized form is seen most often.¹

ETIOLOGY AND PATHOPHYSIOLOGY

• Benign cutaneous, inflammatory disorder of unknown origin.¹

• Disease may be self-limiting, but may persist for many years.

• Reported associations include diabetes mellitus, viral infections (including HIV), Borrelia and streptococcal infections, insect bites, lymphoma, tuberculosis, and trauma.^2,3

• One proposed mechanism for GA is a delayed-type hypersensitivity reaction as a result of T-helper–type cell (Th)-1 lymphocytic differentiation of macrophages. These macrophages become effector cells that express tumor necrosis factor (TNF)-α and matrix metalloproteinases. The activated macrophages are responsible for dermal collagen matrix degradation.⁴

• An association between high expression of gil-1 oncogene and granulomatous lesions of the skin, including GA, has been established.⁵

RISK FACTORS

The only identifiable risk factor is being a woman. There are several associations, but nothing has been shown to be causative.

DIAGNOSIS

CLINICAL FEATURES

Annular lesions have raised borders that are skin-colored to erythematous (see Figures 182-1 and 182-2). The rings may become hyperpigmented or violaceous (see Figure 182-2B). There is often a central depression within the ring. These lesions range from 2 mm to 5 cm. Although the classical appearance of GA is annular, the lesions may be arcuate instead of forming a complete ring (Figure 182-3). Most importantly, there should be no scaling as seen in tinea corporis (ringworm).

TYPICAL DISTRIBUTION

Each of the four types of GA has a different distribution. Localized and disseminated GA differ only in that disseminated lesions can spread to the trunk and neck and may be more pronounced in sun-exposed areas.⁶

• Localized—This is the most common form of GA, affecting 75% of GA patients.¹ It typically presents as solitary lesions on the dorsal surfaces of extremities, especially of hands and feet (Figure 182-4).

• Disseminated or generalized—Adults are most affected by this form, which begins in the extremities and can spread to the trunk and neck (Figure 182-5).

• Perforating—Children and young adults present with 1 to hundreds of 1- to 4-mm annular papules that may coalesce to form a typical annular plaque. Although this form can appear anywhere on the body, it has an affinity for extremities, especially the hands and fingers.⁷ The papules may exude a thick and creamy or clear and viscous fluid.

• Subcutaneous—These lesions present as rapidly growing, nonpainful, subcutaneous or dermal nodules on the extremities, scalp, and forehead. Subcutaneous GA mainly affects children, with a mean age of 3.9 years (Figure 182-6).⁶ These lesions are often ill defined and less discrete.

LABORATORY STUDIES

Often a diagnosis of GA is made on clinical presentation alone, without the need for biopsy. Subcutaneous GA may be an exception, as the unusual appearance may be mistaken for a rheumatoid nodule. Histologic examination reveals an increase of mucin, which is a hallmark of GA. There is also a dense infiltrate of histiocytes in the mid-dermis and sparse perivascular lymphocytic infiltrate. The histiocytes are either organized as palisading cells lining a collection of mucin or as a diffuse interstitial pattern. There are no signs of epidermal change.³

DIFFERENTIAL DIAGNOSIS

• Tinea corporis has a raised, scaling border and can present on any body surface. KOH preparation reveals hyphae with multiple branches (see Chapter 144, Tinea Corporis).

• Erythema annulare centrifugum has an affinity for thighs and legs. The diameter of these lesions can expand at a rate of 2 to 5 mm/day and may present with a trailing scale inside the advancing border.² Biopsy is helpful to differentiate this condition from GA, but may be made on clinical findings alone as GA does not have scale (see Chapter 215, Erythema Annulare Centrifugum).

• Sarcoidosis—Often presents as red-brown dermal papules without scale on the head and neck. Biopsy will help distinguish sarcoidosis from GA (see Chapter 184, Sarcoidosis).

• Nummular eczema presents commonly on extremities, but is almost always associated with scaling plaques and intense itching (see Chapter 154, Nummular Eczema).

• Pityriasis rosea often has oval lesions with a trailing collarette of scale. The lesions are minimally raised and have scale that is absent in GA (see Chapter 159, Pityriasis Rosea).

• Rheumatoid nodules may mimic appearance of subcutaneous GA. These nodules are often seen over the elbows, fingers, and other joints in a patient with joint pains and other clinical signs of arthritis (see Chapter 99, Rheumatoid Arthritis). Rheumatoid nodules have fibrin deposition on histologic examination, in contrast to mucin in GA.

MANAGEMENT

The evidence for various treatments is at best a small series of cases that are not randomized controlled trials. This disease is asymptomatic, and treatments only improve cosmetic appearance. Many patients may want intervention, as diffuse lesions can cause psychological distress. Although GA will eventually resolve, some treatments may cause pigment change or atrophy that might be permanent. Several of the treatments below have shown promise, but these treatments may appear to work when in fact the resolution was natural.

LOCALIZED GA

FIRST LINE

• In a retrospective study of children with localized GA (mean age: 8.6 years), 39 of 42 presented with complete clearance within 2 years. The average duration was 1 year. Researchers of this study consider most treatments unnecessary because of the self-limiting nature of this variation.⁷ One treatment option is watchful waiting.⁸ SORⒷ

• Intralesional corticosteroids can be injected into GA lesions with resolution of the area injected (see Figure 182-1). Inject directly into the ring itself with 3 to 5 mg/mL triamcinolone acetonide (Kenalog) using a 27-gauge needle. SORⒸ A large completed ring may take 4 injections to reach 360 degrees of the circle. The major complications include hypopigmentation (see Figure 182-2A) and skin atrophy at the injected sites.

SECOND LINE

• Cryotherapy was studied using nitrous oxide for 9 patients and liquid nitrogen for 22 patients. The results showed 80% clearing after a single freeze; however, 4 of 19 patients treated with liquid nitrogen developed atrophic scars when lesions were larger than 4 cm. All patients developed blisters.⁹ Cryoatrophy may possibly be prevented by avoiding freeze–thaw cycles greater than 10 seconds and not overlapping treatment areas.¹⁰ SORⒸ

• A 53-year-old Hispanic woman with GA on the dorsal surface of both hands agreed to treatment with cryotherapy on the right hand and intralesional steroids on the left hand (Figure 182-7). Cryotherapy was performed using a 9- to 10-second freeze time and a single freeze. The intralesional injections were performed with a 30-gauge needle and 5 mg/mL triamcinolone (10 mg/mL diluted 1:1 with 1% lidocaine). During the treatment the patient rated the pain from cryotherapy as 9 out of 10 and intralesional steroid 2 out of 10. Figure 182-7 shows the initial lesions and final results after 1 month. The patient was happy with the results of intralesional steroid and disappointed with the results of the cryotherapy. The lesion treated with cryotherapy did not resolve, and spotted areas of hyperpigmentation and hypopigmentation occurred. Upon questioning, the patient states that the lesion treated with cryotherapy was painful for many days, whereas she had no residual pain from the lesion treated with intralesional steroid. The patient then asked for the two remaining lesions on her right hand to be injected with steroid. Although this is a single case example, we could find no published studies of a head-to-head comparison between these commonly used methods for local treatment of GA.

GENERALIZED/DISSEMINATED GA

• This variant is more difficult to treat and often has a longer duration than localized GA. Many treatments have been claimed to be effective, but the studies touting these treatments have small sample sizes and were not randomized.

FIRST LINE

• Recent case reports show that generalized disease responds well to antimalarial treatment. In a retrospective review of patients treated for generalized granuloma annulare, 10 of 18 patients improved after 3 months of treatment with hydroxychloroquine therapy 400 mg daily; by 6 months of therapy most lesions had resolved.¹¹ SORⒸ

• Pentoxifylline, a phosphodiesterase inhibitor, has been used to treat generalized GA with good results.^12,13 Although the mechanism of action on treatment is unknown, it may be related to the TNF-α inhibition. Treatment with 400 mg three times a day provided impressive improvement in three months.¹³ SORⒸ

• The combination of rifampin 600 mg, ofloxacin 400 mg, and minocycline 100 mg successfully treated 6 patients with granuloma annulare. All patients had complete clearance after 3 to 5 months of treatment.¹⁴ SORⒸ

• Successful treatment of 6 patients with GA was achieved with 100 mg of dapsone, once a day. Complete clearance in all patients took between 4 weeks and 3 months.¹⁵ SORⒸ

• UVA1 phototherapy provided good or excellent results in 10 of 20 patients with disseminated GA. In patients with only a satisfactory treatment response, the disease reappeared soon after phototherapy was discontinued.¹⁶ SORⒸ

• Adalimumab resulted in rapid improvement of granuloma annulare lesions in 7 patients.¹⁷ Three patients remained in remission after discontinuing therapy, while 2 patients had recurrence. When the patients with recurrent disease were placed back on adalimumab, their lesions cleared again within 11 weeks. SORⒸ

SECOND LINE

• In a study of 4 patients, topical 5% imiquimod cream was effective when used once daily for an average of 2 months. After discontinuing treatment, 3 patients went an average of 12 months without recurrence; the fourth patient had a recurrence 10 days after treatment stopped, but after an additional 6 weeks of applying cream once daily, he was lesion-free for 18 months.¹⁸ SORⒸ

• Four patients were treated with twice-daily topical application of 0.1% tacrolimus ointment for 6 weeks; all reported improvement after 10 to 21 days. At treatment conclusion, two patients had complete clearance and the other two had marked improvement.¹⁹ SORⒸ

• Treatment with 0.5 to 1 mg/kg of isotretinoin daily has produced some positive results across multiple small studies; however, because of the potential for adverse effects, this option should be reserved for the most severe, nonresponsive cases in patients who are at low risk for the adverse effects of isotretinoin.²⁰ SORⒸ

• Three patients were treated with vitamin E 400 IU daily and zileuton 2400 mg daily. All responded within 3 months with complete clinical clearing.²¹ SORⒸ

PERFORATING, SUBCUTANEOUS

• Although we could find no specific data to inform the treatment of these less-common types of GA, treatments for both localized and disseminated GA could be applied based on clinical judgment along with patient's severity and preferences.

PROGNOSIS

In 50% of cases there is spontaneous resolution within 2 years; however, recurrence rate is as high as 40%.²² Patients with skin of color may have postinflammatory hyperpigmentation once the papules and plaques resolve.

FOLLOW-UP

Follow-up visits should be offered to patients who want active treatment.

PATIENT EDUCATION

It is important to reassure patients that this disease is self-limiting. Despite a displeasing appearance, the best treatment may be to let lesions resolve naturally. Numerous individual case studies and treatments have been attempted without consistent success. Treatments may produce side effects that are equally as unwanted, but more permanent, than the GA.

REFERENCES

PATIENT STORY

A 32-year-old man was diagnosed with Crohn disease 10 years prior to his visit for these nonhealing leg ulcers (Figure 183-1). The patient experienced minor trauma to his lower leg 1 year ago and these ulcers developed (pathergy). Multiple treatments have been tried with partial success, but the ulcers persist.

INTRODUCTION

Pyoderma gangrenosum (PG) is an uncommon ulcerative disease of the skin of unknown origin. It is a type of neutrophilic dermatosis—an inflammatory neutrophilic dermatosis—and is frequently associated with other systemic diseases.¹

EPIDEMIOLOGY

• PG occurs in approximately 1 person per 100,000 each year.²

• A published case series reported a mean age between 50 and 63 years.³ All ages may be affected.

• No racial predilection is apparent.

• A slight female predominance may exist.

ETIOLOGY AND PATHOPHYSIOLOGY

• Etiology is poorly understood. It has no infectious etiology and no tissue-related vascular gangrene.¹

• Pathergy (initiation at the site of trauma or injury) is a common process, and it is estimated that 30% of patients with PG experienced pathergy.²

• Associated systemic diseases such as inflammatory bowel disease (IBD), hematologic malignancy, and rheumatoid arthritis and solid tumors have been documented in 33% to 75% of patients. The rest are idiopathic.^1,4

• It associated with ulcerative colitis (5%–12%) and to a lesser extent Crohn disease (1%–2%) (Figures 183-2 and 183-3).¹

• PG is thought to be autoimmune resulting from defects in cell-mediated immunity, neutrophil and monocyte function, and humoral immunity. Biopsies usually show a polymorphonuclear cell infiltrate with features of ulceration, infarction, and abscess formation.¹

• PG also can be induced by drugs such as isotretinoin, propylthiouracil, granulocyte colony-stimulating factor, sunitinib, and cocaine.⁵

RISK FACTORS

• Ulcerative colitis^4,6.

• Crohn disease.

• Polyarthritis (seronegative or seropositive).

• Hematologic diseases/disorders such as leukemia (predominantly myelocytic).

• Monoclonal gammopathies (primarily immunoglobulin A).

• Psoriatic arthritis and rheumatoid arthritis (Figure 183-4).

• Hepatic diseases (hepatitis and primary biliary cirrhosis).

• Immunologic diseases (lupus erythematosus and Sjögren syndrome).

DIAGNOSIS

CLINICAL FEATURES

• Typically classical PG presents with a deep painful ulcer with a well-defined border, which is usually violet or blue. The color has also been described as the color of gunmetal (Figure 183-5). The ulcer edge is often undermined, and the surrounding skin is erythematous and indurated (Figure 183-6). It usually starts as a pustule with an inflammatory base, an erythematous nodule, or a hemorrhagic bulla on a violaceous base. The central area then undergoes necrosis to form a single ulcer.⁶ Classic PG is characterized by a deep ulceration with a violaceous border that overhangs the ulcer bed. These lesions of PG most commonly occur on the legs (see Figures 183-1, 183-3, and 183-4).⁴ The lesions are painful and the pain can be severe.⁴ Patients may have malaise, arthralgia, and myalgia.

• Vesicular-bullous PG variant most commonly presents on the face and the upper extremities, especially the dorsum of the hands. It occurs most often in association with infections, drug use, or acute myelogenous leukemia.¹

  • Superficial granulomatous/vegetative PG has a vesiculopustular component (Figure 183-7). It is more benign and is erosive or superficially ulcerated, and most often occurs on the dorsal surface of the hands, the extensor parts of the forearms, or the face.⁴

• Other variants:

  • Peristomal PG may occur around stoma sites. This form is often mistaken for a wound infection or irritation from the appliance.⁷

  • Vulvar or penile PG occurs on the genitalia and must be differentiated from ulcerative sexually transmitted diseases (STDs) such as chancroid and syphilis.⁴

  • Intraoral PG is known as pyostomatitis vegetans. It occurs primarily in patients with IBD.⁴

TYPICAL DISTRIBUTION

• Most commonly seen on the legs and hands, but can occur on any skin surface including the genitalia, and around a stoma. PG can also be seen on the face and trunk (Figures 183-5 and 183-8).

LABORATORY TESTING

• Complete blood count (CBC), urinalysis (UA), and liver function tests (LFTs) should be obtained. Order a hepatitis profile to rule out hepatitis.⁴ Systemic disease markers may be elevated if associated conditions exist, that is, erythrocyte sedimentation rate (ESR), antinuclear antibody (ANA), and rheumatoid factor. Obtain rapid plasma reagin (RPR), protein electrophoresis, and skin cultures as indicated. Consider culturing the ulcer/erosion for bacteria, fungi, atypical Mycobacteria, and viruses.⁴

• If GI symptoms exist, perform or refer for colonoscopy to look for IBD.

BIOPSY

• Biopsy an active area of disease along with the border. A punch biopsy is preferred (4-mm punch is adequate). Although there are no specific pathologic signs of PG, the biopsy can be used to rule out other causes of ulcerative skin lesions.¹

• The pathologist may be able to confirm your clinical impression. Biopsy of the earliest lesions reveal a neutrophilic vascular reaction. Fully developed lesions exhibit dense neutrophilic infiltrate, and some lymphocytes and macrophages surrounding marked tissue necrosis. Ulceration, infarction of tissue, and abscess formation with fibrosing inflammation at the edge of the ulcer may be seen.^1,8

DIFFERENTIAL DIAGNOSIS

• PG is sometimes a diagnosis of exclusion, diagnosed with successful wound healing following immunosuppressant therapy.^{9, 1} When misdiagnosed it is often confused for vascular occlusive or venous disease, vasculitis, cancer, primary infection, drug-induced or exogenous tissue injury, and other inflammatory disorders.¹⁰ Biopsy of a questionable lesion may be the only way to ultimately distinguish PG as the cause of ulcerative skin lesions.

• Ulcerative STDs, such as chancroid and syphilis, can resemble vulvar or penile PG. These STDs are more common than PG and should be diagnosed with appropriate tests, including RPR and bacterial culture for Haemophilus ducreyi. If these tests are negative, then PG should be considered. RPR should also be repeated in 2 weeks if it is initially negative at the start of a chancre—it takes some weeks to become positive and syphilis is easily treatable (see Chapter 225, Syphilis).

• Acute febrile neutrophilic dermatosis (Sweet syndrome) is a neutrophilic dermatosis like PG, but the patients are generally febrile with systemic symptoms (Figure 183-9). The diagnosis of Sweet syndrome is made when the patient fulfills 2 of 2 major criteria and 2 of 4 minor criteria. The 2 major criteria are (a) an abrupt onset of tender or painful erythematous plaques or nodules occasionally with vesicles, pustules, or bullae, and (b) predominantly neutrophilic infiltration in the dermis without leukocytoclastic vasculitis. Minor criteria include specific preceding or concurrent medical conditions, fever, abnormal lab values including leukocytosis and an elevated sedimentation rate, and a rapid response to systemic steroids.

• Systemic vasculitis is perhaps the most difficult to differentiate, but history of minor trauma in the area preceding lesion formation (pathergy) and undermining of the violaceous border should lead one toward the diagnosis of PG.¹⁰

• Ecthyma is a type of impetigo in which ulcers form. Bacterial cultures will be positive and this disease should respond to cephalexin or other oral antibiotics (see Chapter 122, Impetigo).

• Brown recluse spider bites can easily resemble PG when they ulcerate. Any spider bite can ulcerate and become necrotic like PG (Figure 183-10). The history of a spider bite can help differentiate this from PG.

• Sporotrichosis is a fungal infection that often starts from an injury while gardening with roses. It is usually on the arm or hand and can resemble PG. Use fungal culture to diagnose this when the history suggests this as the diagnosis. Oral antifungal medications can treat this (Figure 183-11).

• Squamous cell carcinoma with ulcerations may look like PG. Its diagnosis requires a biopsy. If the ulcer is on sun-exposed area, squamous cell carcinoma should be considered. A shave or punch biopsy can be used to diagnose this malignancy (see Chapter 178, Squamous Cell Carcinoma).

• Venous insufficiency ulcers are typically seen around the medial malleolus, and the most severe of these ulcers resemble PG (Figure 183-12). The presence of signs and symptoms of vascular insufficiency should help differentiate this from PG (see Chapter 54, Venous Insufficiency).

• Mycosis fungoides is a cutaneous T-cell lymphoma that can ulcerate and resemble PG. Use tissue biopsy to differentiate these two conditions (see Chapter 180, Cutaneous T-Cell Lymphoma).

MANAGEMENT

FIRST LINE

• Perform appropriate wound care including cleansing, preventing secondary infections (mainly to prevent deeper infection), and providing moist wound healing.¹

• At each visit, measure and document the lesion's depth, length, and width to track treatment progression.¹¹

• Surgical debridement is contraindicated, as pathergy occurs in 25% to 50% of cases and surgery will make the lesions worse. SORⒷ

• Patients frequently are in pain from the lesions, so treatment is aimed at pain relief as well as healing the skin lesions.

• Therapy directed at the underlying disease (often IBD), when present, that usually results in healing. Treatment with steroids is also often necessary.¹¹ SORⒷ

• Topical medications are first-line therapy in cases of localized PG that are not severe. Start with potent corticosteroid ointments or tacrolimus ointment.^11,12 SORⒷ

• Small or indolent ulcers can be managed with topical steroid creams. SORⒸ

• Intralesional injections with corticosteroids are also an option.^11,12 SORⒷ

• Systemic treatment with oral corticosteroids, such as methylprednisolone (1 g/day IV for 3 days) or prednisone (0.5 to 1 mg/kg per day) or oral cyclosporine (e.g., 5 mg/kg per day) alone or together appears to be effective (in the absence of controlled trials) in many cases and should be considered first-line therapy.^7,12 SORⒷ Response is usually rapid, with stabilization of the PG within 24 hours.¹³

SECOND LINE

• In steroid-refractory PG associated with IBD, infliximab was effective in case series and a small placebo-controlled trial.^14,15 SORⒷ Other biologic therapies reported include alefacept, etanercept, efalizumab, and adalimumab.¹¹ SORⒸ

• Cyclosporine (2.5–5.0 mg/kg per day) is used as second-line and steroid-sparing treatment.¹⁶ SORⒶ

• To date, case reports have been published that show therapeutic efficacy of dapsone (100 mg/day), azathioprine (50 to 150 mg/day), 6-mercaptopurine, mycophenolate mofetil (1 to 2 g twice daily), cyclophosphamide (2 to 3 mg/kg per day), and tacrolimus (0.1 mg/kg per day).^12,17 SORⒸ

• The TNF-α antagonists (etanercept, adalimumab, infliximab) have been reported effective in case reports. SORⒸ One small randomized controlled infliximab study showed benefit in 70% of patients.¹⁸ SORⒸ

REFERRAL

In many cases, referral to a dermatologist is needed.

PROGNOSIS

• The prognosis of PG is variable, with residual scarring and recurrences being common.

• Although many patients improve with initial immunosuppressive therapy, patients may follow a refractory course and require multiple therapies.

FOLLOW-UP

• All patients suspected of having PG need close and frequent follow-up to obtain a definitive diagnosis and treat this challenging condition.

PATIENT EDUCATION

• PG is a rare ulcerative skin condition that is poorly understood.

• A skin biopsy is needed to rule out other diagnoses.

• Most treatments are empirical and based on small studies.

• The risks and benefits of steroids and/or other immunosuppressive medications need to be explained.

• Surgical treatments are contraindicated.

REFERENCES

PATIENT STORY

A 42-year-old man presents with "multiple bumps" that had been growing on his scalp, the back of the neck, and on preexisting scars (Figure 184-1). These lesions started developing slowly over a period of 1 year. The differential diagnosis of these lesions included cutaneous sarcoidosis, acne keloidalis nuchae, and pseudofolliculitis barbae. A punch biopsy was performed and the diagnosis of sarcoidosis was made.

INTRODUCTION

Sarcoidosis is a multisystem granulomatous disease most commonly involving the skin, lungs, lymph nodes, liver, and eyes. The condition more commonly affects patients of African descent compared to Caucasian patients. Diagnosing cutaneous sarcoidosis is critical, as 30% of these patients are later found to have systemic involvement. In addition, recent evidence has shown that approximately 25% of autopsies performed on patients with sarcoidosis revealed cardiac involvement.¹ Nevertheless, the diverse presentations of cutaneous sarcoidosis in addition to variants of specific sarcoidosis syndromes can make for a diagnostic challenge.

SYNONYMS

• Lupus pernio (cutaneous sarcoidosis).

• Darier-Roussy disease (subcutaneous sarcoidosis).

• Löfgren syndrome (erythema nodosum, hilar adenopathy, fever, arthritis).

EPIDEMIOLOGY

• Cutaneous manifestations occur in approximately 25% of systemic sarcoidosis patients.

• In approximately one third of cases, cutaneous lesions are the first signs of systemic sarcoidosis.²

• In the United States, the annual incidence is estimated at 35.5 per 100,000 persons of African descent and 10.9 per 100,000 Caucasians.³

• The ratio of patients with only cutaneous sarcoidosis versus multisystem involvement is 1:3.

• Specific cutaneous involvement is most common in older, female patients of African descent (Figures 184-2 and 184-3).

• Common types of cutaneous lesions seen in sarcoidosis include erythema nodosum (EN); papular or plaque type, lupus pernio, cutaneous or subcutaneous nodules, and infiltrative scars.

• EN occurs in 3% to 34% of patients with sarcoidosis and is the most common associated skin finding (see Chapter 186, Erythema Nodosum).

• Sarcoidosis-related EN is more prevalent in Caucasians, especially Scandinavians. EN also has a predilection for Irish and Puerto Rican populations.

• EN occurs between the second and fourth decades of life, more commonly in women.

• Other nonspecific lesions of sarcoidosis reported include erythema multiforme, calcinosis cutis, prurigo, and lymphedema. Nail changes can include clubbing, onycholysis, subungual keratosis, and dystrophy, with or without underlying changes in the bone (cysts).

ETIOLOGY AND PATHOPHYSIOLOGY

• Sarcoidosis is a granulomatous disease of unknown etiology involving multiple organ systems.

• It is thought that a combination of environmental exposures and host genetic factors affecting immune response are involved in the pathophysiology of sarcoidosis.³

• Microscopically, sarcoid lesions are characterized by the presence of circumscribed granulomas of epithelioid cells with little or no caseating necrosis, although fibrinoid necrosis is not uncommon.

• Granulomas are usually in the superficial dermis but may involve the thickness of dermis and extend to the subcutaneous tissue. These granulomas are called "naked" because they have only a sparse lymphocytic infiltrate at their margins.

RISK FACTORS

• Positive family history.

• African descent.

• Obesity.⁴

DIAGNOSIS

There is no singular definitive diagnostic test for sarcoidosis because of the myriad presentations of the disease. Rather, diagnosis is dependent on the constellation of clinical features, laboratory studies, imaging, and pathology via lesion biopsy.

CLINICAL FORMS OF DISEASE

Cutaneous lesions of the disease are either "specific" to sarcoidosis or "nonspecific," denoting a systemic immunologic response to a sarcoidosis lesion found elsewhere in the body.

• Specific:

  • These lesions are typically noncaseating granulomas, with no evidence of infection, foreign body, or other causes.

  • May be disfiguring, but usually are nontender and rarely ulcerate.

  • Maculopapular type is most common with red-brown or purplish papules on the face, neck, upper back, and limbs (Figure 184-4).

  • Lupus pernio is distinctive as it presents as purplish lesions resembling frostbite (or lupus) covered with shiny skin, typically affecting nose, cheeks, ears, and lips and distal extremities (Figures 184-2, 184-3, and 184-5).

  • Lupus pernio may occur as a syndrome involving upper respiratory tract with pulmonary fibrosis, or may be associated with chronic uveitis and bone cysts.

  • Annular or circinate type sarcoidosis lesions appear ribbon-like, with mild scaling, yellowish-red in color, centrifugal progression, and central healing and depigmentation (see Figure 184-1).

  • Plaque sarcoidosis is typically chronic, occurring over the forehead, extremities, and trunk (Figure 184-6). It may be hypopigmented and can heal without scarring.

  • Advanced systemic sarcoidosis typically presents with nodular cutaneous and subcutaneous plaques that are skin-colored or violaceous without epidermal involvement (Figure 184-7).

  • Sarcoid granulomas may also infiltrate areas of old scars damaged by trauma, radiation, surgery, or tattoo (Figures 184-8 and 184-9). Lesions may be tender and appear indurated with red or purple discoloration.

• Nonspecific:

  • EN lesions are the most common nonspecific lesions of sarcoidosis.

  • EN lesions are not usually disfiguring, but tender to touch, especially when they occur with fever, polyarthralgias, and sometimes arthritis and acute iritis.

  • EN appears abruptly with warm, tender, reddish nodules on the lower extremities, most commonly the anterior tibial surfaces, ankles, and knees.

  • EN nodules are 1 to 5 cm, usually bilateral, and evolve through color stages: first bright red, then purplish, and last a bruiselike yellow or green appearance.

  • EN bouts occur with fatigue, fever, symmetrical polyarthritis, and skin eruptions that typically last 3 to 6 weeks, with more than 80% of cases resolving within 2 years.⁴

  • EN is seen in the setting of Löfgren syndrome, appearing with hilar lymphadenopathy (most often bilaterally), and occasionally anterior uveitis and/or polyarthritis.

  • Löfgren syndrome is associated with right paratracheal lymph node involvement seen on X-ray.

  • Ulceration is typically not observed in EN, which heals without scarring.

  • Other nonspecific lesions of sarcoidosis include lymphedema, calcinosis cutis, prurigo, and erythema multiforme.

  • Nail changes seen in sarcoidosis include clubbing, onycholysis, and subungual keratosis.

LABORATORY STUDIES

• Complete blood count (CBC) count with differential:

  • Leukopenia (5%–10%) and/or thrombocytopenia may be seen.

  • Eosinophilia occurs in 24% of patients, and anemia occurs in 5% of patients.

  • Hypergammaglobulinemia (30%–80%), positive rheumatoid factor, and decreased skin test reactivity.

  • Autoimmune hemolytic anemia and hypersplenism can occur in some patients, although rare.

  • Hypocapnia and hypoxemia may be present in certain patient populations and may become worse with exercise.

• Serum calcium and 24-hour urine calcium levels:

  • Hypercalciuria has been found in 49% of patients in some studies, whereas 13% of patients had hypercalcemia.

  • Hypercalcemia occurs in sarcoidosis because of increased intestinal absorption of calcium that results from overproduction of a metabolite of vitamin D by pulmonary macrophages.

• Serum angiotensin-converting enzyme (ACE) level is elevated in 60% of patients:

  • Serum ACE levels are helpful in monitoring disease activity and treatment response. ACE is derived from epithelioid cells of the granulomas; therefore, it reflects granuloma load in the patient.

• Serum chemistries, such as alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, blood urea nitrogen (BUN), and creatinine levels. These levels may be elevated with hepatic and renal involvement.

• Other—Elevated erythrocyte sedimentation rate, elevated antinuclear antibodies (30%), diabetes insipidus, and renal failure may be noted.

IMAGING STUDIES

• Chest X-ray (CXR):

  • Radiographic involvement of the chest is seen in almost 90% of patients.

  • Stage I disease shows bilateral hilar lymphadenopathy (BHL).

  • Stage II disease shows BHL plus pulmonary infiltrates.

  • Stage III disease shows pulmonary infiltrates without BHL.

  • Stage IV disease shows pulmonary fibrosis.

• CT of the thorax may demonstrate lymphadenopathy or granulomatous infiltration. Other findings may include small nodules with a bronchovascular and subpleural distribution, thickened interlobular septae, honeycombing, bronchiectasis, and alveolar consolidation.

• Pulmonary function tests—Evidence of both restrictive abnormalities and obstructive abnormalities may be found.

BIOPSY

• A 4-mm punch biopsy is adequate to obtain a sample of skin that includes dermis.

• If EN nodules are deep, a deep punch biopsy should also include subcutaneous fat.

• Biopsy specimens are sent for histologic examination. If an infection (deep fungal, mycobacterium) is suspected, some tissue should be sent in a sterile urine cup for tissue cultures.

DIFFERENTIAL DIAGNOSIS

• Granulomatous skin disease (Figure 184-10).

  • Granuloma annulare (GA) is also a granulomatous skin disease, which appears in single or multiple rings in adults and children (see Chapter 182, Granuloma Annulare).

  • Rheumatoid nodules—These usually appear in the context of a diagnosed rheumatoid arthritis with joint disease present (see Chapter 99, Rheumatoid Arthritis).

  • Granulomatous mycosis fungoides—This is a type of cutaneous lymphoma with many clinical forms including granuloma formation (see Chapter 180, Cutaneous T-Cell lymphoma).

• Maculopapular type:

  • Lupus vulgaris—This is a type of cutaneous involvement with Mycobacterium tuberculosis.

  • Syringoma—These are small firm benign adnexal tumors usually appearing around the upper cheeks and lower eyelids.

  • Xanthelasma—These are the most common type of xanthomas. They are benign yellow macules, papules, or plaques often appearing on the eyelids. Approximately half of patients with xanthelasma have a lipid disorder (see Chapter 232, Hyperlipidemia and Xanthomas).

  • Lichen planus—This is a very pruritic skin eruption with pink to violaceous papules and plaques. It may present in different body locations, but the most common areas are the wrists and ankles (see Chapter 160, Lichen Planus).

  • Granulomatous rosacea—This is a variant of rosacea made of uniform papules involving the face.

  • Acne keloidalis nuchae—This is commonly seen in dark-skinned patients. It presents with multiple perifollicular papules and nodules. The most common location is the back of the neck at the hairline (see Chapter 120, Pseudofolliculitis and Acne Keloidalis Nuchae).

  • Pseudofolliculitis barbae—This is most commonly seen in patients with darker skin color, triggered by ingrown hair involving the beard area (see Chapter 120, Pseudofolliculitis and Acne Keloidalis Nuchae).

• Annular or circinate type of sarcoidosis (Figure 184-11):

• Granuloma annulare—Annular type (previously described above; see Chapter 182, Granuloma Annulare).

• Annular form of necrobiosis lipoidica—A granulomatous disease with areas of necrobiosis. This is usually seen on the pretibial areas of patients with diabetes. But not all patients have diabetes (see Chapter 231, Necrobiosis Lipoidica).

• These two entities may be differentiated histologically.

• Nodular cutaneous and subcutaneous type:

  • Morphea—Also known as localized scleroderma caused by excessive collagen deposition in the dermis or subcutaneous tissue leading to the formation of nodules (see Chapter 190, Scleroderma and Morphea).

  • Epidermal inclusion cyst—This is an encapsulated keratin-filled nodule of different sizes often found in the subcutaneous tissue. A central pore or punctum is often noted on examination of the overlying epidermis.

  • Lipoma—These are soft nodules of different sizes composed of mature fat cells and often found in the subcutaneous tissue.

  • Metastatic carcinoma—These nodular lesions often present in the context of a diagnosed primary carcinoma of other internal organs.

  • Foreign-body granuloma—This is usually localized to the area of introduction of the foreign body into the skin.

MANAGEMENT

FIRST LINE

• Cutaneous involvement of sarcoidosis is not life-threatening, so the major rationale for treatment is to prevent or minimize disfigurement. Cosmetic issues are particularly important on the face (Figure 184-12A). Also, the lesions can be painful.

• Corticosteroids are the mainstay of treatment.^3,5-10 SORⒷ

• Limited cutaneous disease responds to very high-potency topical corticosteroids, or intralesional triamcinolone (repeated monthly as needed).^5,9 SORⒷ

SECOND LINE

• Photochemotherapy (psoralen UVA) is successful in erythrodermic and hypopigmented lesions. SORⒸ

• Patients with lupus pernio may benefit from pulsed-dye or carbon dioxide laser treatments. SORⒸ

• Resistant lesions to topical therapy or large and diffuse lesions require prednisone.^7,8,10 SORⒷ

• To prevent complications from long-term treatment by steroids, hydroxychloroquine or chloroquine can be used as a steroid-sparing agent.¹⁰ SORⒸ

• Other combinations that have been successful in chronic cutaneous disease and lung disease are methotrexate or azathioprine with low-dose prednisone.¹⁰ SORⒸ

THIRD LINE

• Agents such as cyclophosphamide and cyclosporin are also used, but with caution because of severe drug toxicity.¹¹ SORⒸ

• Tumor necrosis factor (TNF)-α monoclonal antibody therapy has shown a response rate of up to 79% after 1 year of therapy for patients with cutaneous sarcoidosis (Figure 184-13).¹² SORⒸ

• In addition, evidence has shown that infliximab is efficacious for sarcoidosis with pulmonary,¹³ neurologic, hepatic, muscular, ocular, and cardiac involvement as well.¹⁴

• Adalimumab is another TNF-α monoclonal antibody agent that has shown efficacy especially in manifestations of sarcoidosis of the eye. In addition, this agent has shown efficacy for lung, skin, and bone involvement of the disease.¹⁴

• Both infliximab and adalimumab are considered third-line agents (after steroids and disease-modifying antisarcoid drugs such as methotrexate) for refractory cases of sarcoidosis. However, before starting any of these biologic agents, any infections including latent tuberculosis must be ruled out for fear of reactivation.¹⁴

• Etanercept, another anti-TNF-α biologic agent, is not useful for sarcoidosis given its history of treatment failure in several studies.¹⁴

REFERRAL

• A multidisciplinary approach is imperative in patients with systemic sarcoidosis.

• Patients with eye symptoms should be referred to an ophthalmologist (Figure 184-12B).

• Patients with lung involvement should be referred to a pulmonologist.

• Patients with possible cardiac involvement (a positive history of cardiac symptoms, abnormal ECG or echocardiogram) should be referred to a cardiologist.¹

• Patients with lupus pernio should be referred to ENT for potential airway involvement.

• Results from laboratory work-up may help direct appropriate referral.

PREVENTION AND SCREENING

There are currently no preventative measures established, as the cause remains to be elucidated. Patients presenting with cutaneous sarcoidosis should be screened as clinically indicated depending on concomitant signs and symptoms. Patients placed on long-term oral steroids should be treated appropriately to prevent osteoporosis.

PROGNOSIS

• Patients of African descent tend to have more severe lung disease compared to Caucasian patients at presentation and an overall poorer long-term prognosis.¹⁵

• The presence of EN has been associated with a decreased frequency of respiratory involvement.¹⁵ In addition, EN is associated with an acute course with better prognosis.³

• Lupus pernio, more commonly seen in patients of African descent, indicates a chronic disease course with upper respiratory or nasal mucosa involvement (Figures 184-12 and 184-13).^3,15

• The prognostic value of cutaneous lesions alone remains unclear.¹⁵

FOLLOW-UP

Patients with cutaneous sarcoidosis should be monitored for possible systemic involvement. Regular follow-up is necessary, especially if biologic medications are used.

PATIENT EDUCATION

Inform patients about the risk that systemic sarcoidosis can occur even if the skin is the only area currently involved.

REFERENCES